Clinician/scientist research training is proposed in the area of cell and molecular biology. Class work in basic science and clinical research methodology will be combined with a program of research on vestibular schwannoma (VS). VS are among the most common intracranial lesions and can lead to devastating and debilitating complications, especially in association with Neurofibromatosis 2 (NF2). Current treatment modalities are limited to surgery and radiotherapy, which both carry additional risks to the patient. Development of a tumor-specific pharmacotherapy is highly desireable. The ErbB family of epidermal growth factor receptors and their ligands are critically involved with Schwann cell growth, survival, proliferation, and differentiation. The protein merlin (schwannomin) interacts with ErbB receptors, inhibiting their proliferation and survival signaling. Since NF2 and sporadic VS are associated with loss of functional merlin in the Schwann cell, this strongly implicates ErbB signaling in VS tumorigenesis. Moreover, ErbB pharmacotherapy is successfully used in several forms of cancer. Thus elucidation of the role of ErbB signaling in the pathogenesis of VS will be a critical step in developing pharmacologic agents for VS tumors as well. The proposed research will compare the expression and activation of ErbB signaling components in human vestibular schwannomas (VS) and normal Schwann cells. Also, the effects of activating or inhibiting ErbB signaling on VS and Schwann cell behavior will be evaluated in vitro. Next, whether ErbB signaling status in VS from individual patients, as assessed above, is related to the clinical characteristics of their VS will be determined. Finally, ErbB signaling will be manipulated in VS tumors in vivo, and a strategy for targeting molecular therapies selectively to VS cells will be developed. In accordance with the mission of the NIH, this research is translational in nature, since the ultimate goal is to develop a potential pharmacotherapeutic alternative to surgery and irradiation for VS. The project pairs a strong basic science component with clinical research. It will thus provide an excellent platform for clincian/scientist research training. LAY DESCRIPTION: Vestibular schwannomas (also called acoustic neuromas) are benign tumors of the balance nerve, that can cause hearing loss, dizziness, and facial weakness. Treatment is limited to surgery or radiation. The proposed project investigates the molecular events that cause vestibular schwannomas with the goal of developing a new medical treatment alternative.